Effective methods for the separation and recovery of particular enantiomers of biochemicals such as amines and amino acids, as well as other types of biochemicals, is of great importance in modern technology. This importance is exemplified by the growing need and desire to produce and use optically pure pharmaceuticals and other biochemicals for human and other use. For example, often only one enantiomer of a chemical compound is biologically active or produces a desired effect. Thus, in order for a recipient of a pharmaceutical to receive enough of the biologically active enantiomer, twice the amount of pharmaceutical is generally given (assuming that the enantiomers are represented at about a 50:50 molar ratio). In other cases, an undesired enantiomer may be toxic or produce side effects. For example, the undesired enantiomer of thalidomide has been known to cause severe malformation in children born to pregnant women who took the drug by prescription for the benefits of the desired enantiomer. Therefore, much research has been conducted in order to produce optically or enantiomerically pure pharmaceuticals such that the biologically active or desired enantiomer may be used in essentially pure forms in order to eliminate the drawbacks discussed above.
There are essentially three theoretical methods that may be used to obtain optically pure compounds for pharmaceutical or other use. First, the desired enantiomer may be synthesized in the desired enantiomeric or optically pure form. Unfortunately this method is often impractical because, in many cases, these types of synthesis methods have not been discovered, or alternatively for those that have been discovered, the production cost of making the pure enantiomer has been prohibitive.
The second method involves separating the desired enantiomer from a mixture containing both enantiomers. However, because the enantiomers differ only in chirality, such processes have proven very difficult to carry out. In some instances, these separations have been accomplished by means of crystallization. For example, tartaric acid as a crystallization platform has been used for such a separation. Though this is a somewhat cost effective method, it is useful in only a minority of cases. In most instances, such separations must be performed using a chromatographic stationary phase and a chromatographic method of separation. These types of chromatographic separations have low throughputs and high operating costs.
The third method for chiral separation involves a combination of the two methods described above. In this combination method, an initial chiral intermediate is separated at a relatively high purity followed by additional synthesis steps that further purify the chiral intermediate to a final product without introducing additional chiral impurity.
In general, to overcome the high cost of performing chiral separations, a method that allows for high selectivity of a target enantiomer over its counter-enantiomer is needed. As such, non-chromatographic or equilibrium bind/release separation modes using solid resin phases have been formed to accomplish this result with several additional amines and amino acids that have not been easily separable in non-chromatographic form by previous resins. U.S. Publication No. 2002/0019491, filed on Mar. 8, 2001, the entirety of which is incorporated herein by reference, sets forth previous solid resin phases of sufficient selectivity and/or stability for the separation of several different amines and amino acids. Prior to this, there have not been compositions known to accomplish such an enantiomeric separation function to a degree of purity that is both practical to use and cost effective. This is significant because it is the separation itself that accounts for a large portion of the total cost of making a pure enantiomeric product. Thus, by reducing the separation costs, the final selling price of the pure enantiomer may be reduced.
As stated, some research has been done in producing chiral ligands capable of some selectivity between chiral enantiomers of the same compound. Additionally, electrophoresis has been used as well for such chiral separations. However, both of these methods, i.e. chromatography and electrophoresis, provide only low throughputs, and therefore, are not as desired as that described by the present invention. Some articles have described electrophoresis as a separation method and several other articles have discussed the use of such ligands in chromatographic resin phases. Such patents and articles include: U.S. Pat. Nos. 4,001,279 and 4,043,979 issuing to Cram, D. J.; Dotsevi, G., et al., Chromatographic Optical Resolution through Chiral Complexation of Amino ester Salts by a Host Covalently Bound to Silica Gel, J. Amer. Chem. Soc., 97:5, pp 1259–61 (1974); Bradshaw, J. S., et al., Enantiomeric Recognition of Organic Ammonium Salts by Chiral Dialkyl-, Dialkenyl-, and Tetramethyl-Substituted Pyridino-18-crown-6 and Tetramethyl-Substituted Bis-pyridino-18-crown-6 Ligands: comparison of Temperature-Dependent H NMR and Empirical Force field techniques, J. Org. Chem., Volume 55, pp. 3129–37 (1990); Zhang, et al., Enantiomeric Recognition of Amine Compounds by Chiral Macrocyclic Receptors, Chem. Rev., Volume 97, pp. 3313–61 (1997); Pirkle, W. H. et al., Chiral Stationary Phases for the Direct LC Separation of Enantiomers, Adv. Chromatography, Volume 27, pp. 73–127 (1987); Armstrong, D. W., et al., Macrocyclic Antibiotics as a New Class of Chiral Selectors for Liquid Chromatography, Anal. Chem., Volume 66, pp. 1473–1484 (1994); Armstrong, D. W., et al., Optical Isomer Separation by Liquid Chromatography, Anal. Chem., Volume 59, pp. 84A–91A (1987); Huszthy, P., et al., Enantiomeric Separation of Chiral [α-(1-Naphth)Ethyl]Ammonium Perchlorate by Silica Gel-Bound Chiral Pyridino-18-Crown-6 Ligands, Acta Chim Hung, Volume 131, pp. 445–54 (1994); Pirkle, W. H., et al., Chem. Rev., Volume 89, pp. 347–362 (1989), all of which are incorporated herein by reference.
Outside of the work described in U.S. Publication No. 2002/0019491, high selectivity non-chromatographic separation of amines and amino acids via highly stable covalently attached or coated ligands in three separation stages or less has not been previously demonstrated. Most work in this area discloses procedures for synthesizing either chromatographic resin materials for chiral separations or for synthesizing unbound ligands with chiral selectivity in single phases. Therefore, it would be desirable to provide compositions and methods of separating enantiomers using non-chromatographic separation techniques that allow for much faster separations at much higher quantities while maintaining lower cost basis for the separation. Though U.S. Publication No. 2002/0019491 describes effective non-chromatographic separations for several chiral amines and amino acids, it has since been found that certain β-amino acids and/or large α-amines containing aromatic groups can be separated even more efficiently using particular solvent-coated ligand-bound solid supports not described previously.